The mammalian unfolded protein response: a potential source of novel therapeutic targets in the hypoxic tumour fraction
Review Articles
duration of activation [51, 52]. This concept of a “switch” between adaptation and apoptosis has only recently been seriously investigated, and as such is relatively poorly defined – several recent reviews on the subject have suggested much further research is needed [15, 53-55].
The UPR is a potential therapeutic target in solid cancers
Given the near-ubiquitous activation of the UPR and its importance to cell survival in solid malignancies, interest in small molecule inhibitors as modulators of the UPR and hence novel cancer therapeutics has grown significantly, mostly based on evidence obtained through genetic disruption of the response [56]. Drugs targeting the UPR can be currently classified into two broad categories – those increasing the ER stress in the cell (driving the UPR through to apoptosis) and those inhibiting UPR adaptation pathways. An excellent Figure 2: Hypoxic signaling through the UPR can either lead to stress adaptation or apoptosis. Through a currently undefined mechanism, UPR signaling can lead to two distinct out- example of the former is bortezomib (Velcade), comes for the cell – adaptation to a stressor or apoptosis. Each pathway is generally identified an FDA-approved proteasome inhibitor for late by upregulation of a specific set of genes as indicated, although both sets may be expressed stage multiple myeloma that blocks ERAD and insimultaneously. creases the speed and severity of unfolded protein IRE1 has been observed to modulate apoptosis under UPR buildup in the ER lumen [57, 58]. Several other activation by two mechanisms – through downstream phos- compounds such as sorafenib, paraquat, and ursolic acid have been phorylation of Jun n-terminal kinase (JNK) and activation of shown to increase ER stress and, in the case of paraquat and ursolic IRE1-dependent decay of RNAs (RIDD). In a key study published acid, to activate the IRE1-JNK apoptosis pathway [59-62]. To this in 2000, Urano et al. showed that IRE1 associated with TRAF2 end, an interesting approach utilizing peptides to inhibit the activ(TNF receptor-associated factor 2) to cause the phosphorylation ity of BiP and push the UPR through to apoptosis in a prostate of JNK, which is strongly linked to apoptosis [36-41]. In addition cancer model has been investigated [63]. to association with TRAF2, IRE1 can affect apoptosis through the A recent number of papers have identified small molecule degradation of RNAs through RIDD. RIDD occurs when IRE1 inhibitors of IRE1 and PERK, 2 of the 3 UPR stress transducers. A is hyperactive (i.e. active for a prolonged period of time) and is a majority of the IRE1 inhibitors identified so far are aldehydes that non-specific method of mRNA degradation [42,43]. While RIDD inhibit IRE1 endogenous RNase activity (i.e. XBP1 splicing and could present a survival mechanism (by decreasing translational RIDD), and not IRE1 kinase activity [28, 64-68]. Specific residues load) it is thought of more as a means to apoptosis through the within IRE1 such as Lys599 have been identified as important for degradation of key survival transcripts such as those encoding BiP endonuclease compared to kinase activity [28]. In the context of or XBP1. Interestingly, a recent study illustrated a putative link cancer, IRE1 inhibitors have been shown to exhibit anticancer from mTORC1 to the IRE1-JNK pathway, suggesting that different activity in vitro and in vivo in two separate studies of multiple hypoxia response pathways may be interrelated [44]. myeloma [64, 65]. Given that IRE1 signaling still remains incomPERK is connected to apoptosis through the ATF4-dependent pletely understood, the majority of these molecules are largely used upregulation of CHOP (C/EBP homologous protein), which is as research tools and not as potential therapeutics [69]. considered a proapoptotic transcription factor [45-49]. In a pivotal As a result of PERK lacking the nuclease activity seen with 2004 study, CHOP was shown to induce GADD34, a phosphatase IRE1, inhibitors are generally targeted to the ATP-binding region that specifically dephosphorylates p-eIF2a in a negative feedback important for its kinase activity. In a landmark 2011 study, Wang loop [49]. This returns the ER to a pre-stressed state and promotes and colleagues reported the first pharmacophore model of PERK renewed protein synthesis, which in a continuously stressed sys- to be built, specifically identifying Met7 and Asp144 as required tem is a proapoptotic action. contacts for specific inhibitor binding to the protein [70]. Several As the least studied stress sensor, ATF6 has not been linked other inhibitors of PERK kinase activity are in development as solidly to apoptosis although an isolated study suggests it may me- specific anticancer agents although none have progressed past diate apoptosis through its own unique pathway [50]. mouse model investigation. Given that the UPR activates all three arms differentially and The above options are directed at inhibiting adaptive UPR concomitantly, it has been difficult to elucidate the specific effect of pathways in cancer cells – however, small molecule activators each arm on cell fate. Two recent studies by Lin et al. clearly show targeted at apoptotic UPR pathways instead could present another divergent cell fates under stress when either IRE1 or PERK sig- potential treatment modality. For example, in yeast it has been naling was sustained artificially, suggesting each arm contributes discovered that certain flavonols (flavonoids characterized by a differently to the decision between life and death depending on its 3-hydroxyflavone backbone) activate IRE1 activity [71]. If this can Journal of Undergraduate Life Sciences • Volume 7 • Issue 1 • Spring 2013
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